PROJECT SUMMARY Intellectual disability (ID) is the most frequent cause of developmental disabilities and affects 1-3% of the population. Most cases of ID, unfortunately, are still lacking effective prevention and intervention options. Among the heterogeneous causes of ID, metabolic dysfunctions in the brain are playing an essential role, with a particular emphasis on lipids, which form a fundamental basis for both neurobiology and brain function. Given the extreme complexity of lipid metabolism and the central nervous system, how lipids and which species of them regulate neuronal functions and contribute to the development of ID, however, are still poorly understood. In this context, Acsl4, a gene encoding an isozyme of long chain acyl-CoA synthetase family, was found mutated in X-linked ID or Alport syndrome, thus providing a valuable interface to understand both mental health and lipid metabolism. Due to the lack of effective approaches to perturb it in neurons, ACSL4?s precise functions in the brain are still undetermined. Whether dysregulations of ACSL4 contribute to the development of ID is also unknown. Recently, based on multiple lines of evidence and our preliminary observation, we hypothesize that ACSL4 in hippocampal neurons is essential for neuron development and cognition. We further propose that lacking ACSL4 in the mouse hippocampus affects learning and memory (Aim-1) by dampening synapse formation and synaptic plasticity (Aim-2). Importantly, we postulate that ACSL4 achieves such regulatory functions in the brain by altering lipid metabolism (Aim-3). Through a recent effort to investigate the role of ACSL4 in adipose tissue in vivo, we have established a floxed-Acsl4 conditional mouse model, which allows tissue-specific deletion of the gene in a cre-dependent manner. We then plan to leverage this mouse line to establish a neuron-specific ACSL4 knockout mouse model to assess the above hypotheses. The proposed studies in the current application will discover a novel neurobiological mechanism by which lipid homeostasis orchestrated by ACSL4 regulates synaptic and neural functions in the brain and maintains mental health. A battery of rigorous, comprehensive approaches at molecular, cellular and system levels will be employed. Fulfillment of the research will likely reveal new biology and novel biomarkers relevant to the etiology and treatment of mental disorders and will therefore be of great values in both basic and translational research on mental health.